Breast Cancer Treatments | Encyclopedia MDPI

Breast Cancer Treatments: Comparison

Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Francine Durocher.

Breast cancer (BC) is the most frequent cancer diagnosed in women worldwide. This heterogeneous disease can be classified into four molecular subtypes (luminal A, luminal B, HER2 and triple-negative breast cancer (TNBC)) according to the expression of the estrogen receptor (ER) and the progesterone receptor (PR), and the overexpression of the human epidermal growth factor receptor 2 (HER2). Current BC treatments target these receptors (endocrine and anti-HER2 therapies) as a personalized treatment. Along with chemotherapy and radiotherapy, these therapies can have severe adverse effects and patients can develop resistance to these agents. Moreover, TNBC do not have standardized treatments. Hence it is essential to develop new treatments to target more effectively each BC subgroup.

breast cancer
personalized therapies
molecular subtypes
breast cancer treatment
luminal
HER2
TNBC

1. Introduction

Breast cancer (BC) is the most frequent cancer and the second cause of death by cancer in women worldwide. According to Cancer Statistics 2020, BC represents 30% of female cancers with 276,480 estimated new cases and more than 42,000 estimated deaths in 2020 ^[1].

Invasive BC can be divided into four principal molecular subtypes by immunohistological technique based on the expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) ^[2]. Luminal A BC (ER+ and/or PR+, and HER2-) represents around 60% of BC and is associated with a good prognosis ^[3]. Luminal B BC (ER+ and/or PR+, and HER2+) represents 30% of BC and is associated with high ki67 (>14%), a proliferation marker, and a poor prognosis ^[4]. HER2 BC (ER-, PR-, and HER2+) represents 10% of BC and is also associated with a poor prognosis ^[5]. Lastly, triple-negative BC (TNBC) (ER-, PR-, and HER2-) represents 15–20% of BC and is associated with more aggressivity and worse prognosis compared to other BC molecular subtypes and often occurs in younger women ^[6]. Characteristics of BC by molecular subtypes are described in Figure 1.

Figure 1. Characteristics of breast cancer molecular subtypes. ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth factor receptor 2; TNBC: triple-negative breast cancer. ^a. Frequency derived from Al-thoubaity et al. [12]^[7] and Hergueta-Redondo et al. [13]^[8]. ^b. Grade derived from Engstrom et al. [14]^[9]. ^c. Prognosis derived from Hennigs et al. [15]^[10] and Fragomeni et al. [16]^[11]. ^d. The 5–year survival rate derived from the latest survival statistics of SEER [7]^[12].

The 5-year relative BC-specific survival rate of BC is encouraging with 90.3% for all subtypes and stages. However, for metastatic BC the 5-year relative cancer-specific survival rate is still low: 29% regardless of subtype and can drop to 12% for metastatic TNBC [7]^[12]. This clearly indicates that strategies of treatment for metastatic BC patients are not effective enough to ensure a good survival rate. Thus, it is crucial to find new solutions for the treatment of metastatic BC and especially TNBC.

Treatment choice is based on the grade, stage, and BC molecular subtype to have the most personalized, safe, and efficient therapy. The grade describes the appearance of tumor cells compared to normal cells. It includes tubule differentiation, nuclear pleomorphism, and the mitotic count [8]^[13]. The stage is used to classify the extent of cancer in the body and is defined using the TNM system comprising tumor size, lymph node status, and the presence of metastases [9]^[14]. For non-metastatic BC, the strategic therapy involves removing the tumor by complete or breast-conserving surgery with preoperative (neoadjuvant) or postoperative (adjuvant) radiotherapy and systemic therapy including chemotherapy, and targeted therapy. Targeted therapy comprises endocrine therapy for hormone receptor-positive (HR+) BC and anti-HER2 therapy for HER2+ BC. Unfortunately, there is no available targeted therapy for the TNBC subtype. For metastatic BC the priority is to contain tumor spread as this type of BC remains incurable. The same systemic therapies are used to treat metastatic BC [10]^[15].

Challenges in the treatment of BC including dealing with treatment resistance and recurrence. Indeed, 30% of early-stage BC have recurrent disease, mostly metastases [11]^[16]. Thus, it is crucial to develop new strategic therapies to treat each BC subgroup effectively.

2. Common Treatments for All Breast Cancer Subtypes

In addition to surgery, radiotherapy and chemotherapy are used routinely to treat all BC subtypes ^[17].

2.1. Surgery

The most standard breast surgery approaches are either total excision of the breast (mastectomy), usually followed by breast reconstruction, or breast-conserving surgery (lumpectomy). Lumpectomy entails the excision of the breast tumor with a margin of surrounding normal tissue. The recommended margins status is defined as “no ink on tumor”, meaning no remaining tumor cells at the tissue edge ^[18]. Studies show that total mastectomy and lumpectomy plus irradiation are equivalent regarding relapse-free and overall survival (OS) ^[19]. Contraindications for breast-conserving surgery include the presence of diffuse microcalcifications (suspicious or malignant-appearing), disease that cannot be incorporated by local excision with satisfactory cosmetic result, and ATM (ataxia-telangiesctasia mutated) mutation (biallelic inactivation) ^[18].

2.2. Radiotherapy

Radiation therapy has been used to treat cancer since Röngten discovered the X-ray in 1895 [22]^[20]. High-energy radiations are applied to the whole breast or a portion of the breast (after breast-conservative surgery), chest wall (after mastectomy), and regional lymph nodes [23]^[21]. Postmastectomy radiation to the chest wall in patients with positive lymph nodes is associated with decreased recurrence risk and BC mortality compared to patients with negative lymph nodes [25]^[22]. A radiation boost to the regional node radiation treatment can be incorporated after mastectomy for patients at higher risk for recurrence [26]^[23]. Radiotherapy can be administered concurrently with personalized therapy (anti-HER2 therapy or endocrine therapy).

Radiation therapy is used to treat all BC subtypes, but its implication is more important for TNBC, as there is no personalized therapy for this subtype. It has been shown that radiotherapy benefits TNBC patients both after conserving surgery and mastectomy [39]^[24].

2.3. Chemotherapy

BC chemotherapy comprises several families of cytotoxic drugs, including alkylating agents, antimetabolites and tubulin inhibitors [40]^[25]. Cyclophosphamide is a nitrogen mustard alkylating agent causing breakage of the DNA strands [41]^[26]. The mechanism of action for anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) includes DNA intercalation, thereby inhibiting macromolecular biosynthesis [42]^[27]. Taxanes, including docetaxel and paclitaxel, bind to microtubules and prevent their disassembly, leading to cell cycle arrest and apoptosis [43]^[28].

Chemotherapy can be administered in the neoadjuvant or adjuvant setting and for metastatic BC treatment.

3. Current Personalized Treatments for Breast Cancer: Strengths and Weaknesses

The current strategies of treatment are principally based on the tumor progression and BC molecular subtypes in order to offer the most personalized treatment for BC patients. The algorithm of BC treatment is represented in Figure 2.

Figure 2. Breast cancer treatment flow diagram. (A). Early-stage breast cancer. (B). Metastatic/advanced breast cancer. ^a Neoadjuvant chemotherapy for HR+ BC patients is not systematic. It is mainly administered to luminal B BC patients and/or elder BC patients. HR+: hormone receptors positive; HER2+: human epidermal growth factor receptor 2 positive; TNBC: triple-negative breast cancer; AIs: aromatase inhibitors; T-DM1: trastuzumab-emtansine.

3.1. Endocrine Therapy

Endocrine therapy is the main strategy to treat HR positive invasive BC. The purpose of this therapy is to target the ER directly (selective estrogen receptors modulators and degraders) or the estrogen synthesis (aromatase inhibitors) [67]^[29]. The most common types of endocrine therapy are selective estrogen receptor modulators (SERMs), selective modulators estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs) [68]^[30]. Endocrine therapy mechanism of action and resistance are described in Figure 3.

Figure 3. Endocrine therapy mechanisms of action and resistance. The left part of the figure shows the mechanism of endocrine therapy through aromatase inhibitors, tamoxifen, and fulvestrant. The right part of the figure describes the mechanisms of resistance to endocrine therapy through the epigenetic modifications, the increase of coactivators and cell cycle actors, and the activation of other signaling pathways. Estrogens can go through the plasma membrane by a. diffusion as they are small non-polar lipid soluble molecules; b. binding to membrane ER initiating the activation of Ras/Raf/MAPK and PI3K/Akt signaling pathways which are blocked by tamoxifen. 1: inhibition of ER dimerization; 2: blockage of nucleus access; 3: ER degradation. ER: estrogen receptor; AIB1: amplified in breast cancer 1; IGF-1R: insulin growth factor receptor 1; IGF: insulin growth factor; HER: human epidermal receptors; EGF: epidermal growth factor; HB-EGF: heparin-binding EGF-like growth factor; TGF-α: transforming growth factor alpha; MEK/MAPK: mitogen activated protein kinase; PI3K: phosphoinositide 3-kinase; mTOR: mammalian target of rapamycin; Me: methylation; Ac: acetylation.

3.2. Anti-HER2 Therapy

The overexpression of HER2 is associated with worse survival outcome compared to HR-positive/HER2-negative BC [128,129]^[31][32]. Hence, therapies targeting HER2 are essential to treat HER2-positive BC. The current anti-HER2 therapies comprise antibodies that target specific HER2 epitopes, tyrosine kinase inhibitors (TKIs) and, more recently, antibody-drug conjugates (ADCs) [130]^[33]. Anti-HER2 mechanisms of action and resistance are described in Figure 4.

Figure 4. Anti-HER2 therapy mechanisms of action and resistance. The left part of the figure describes the mechanism of action of anti-HER2 therapy through anti-HER2 antibody (trastuzumab and pertuzumab), tyrosine kinase inhibitors (lapatinib and nerotinib), and the antibody-drug conjugate trastuzumab-emtansine (T-DM1). The right part of the figure describes the mechanism of resistance to anti-HER2 therapy through constitutive active p95^HER2 fragment, activation of other signaling pathways, and rapid recycling of HER2-T-DM1. ADCC: antibody-dependent cellular cytotoxicity; HER2: human epidermal growth factor receptor 2; EGF: epidermal growth factor, HB-EGF: heparin-binding EGF-like growth factor; TGF-α: transforming growth factor alpha; T-DM1: trastuzumab-emtansine; IGF-1R: insulin growth factor receptor 1; IGF: insulin growth factor; HGF: hepatocyte growth factor; MEK/MAPK: mitogen activated protein kinase; PI3K: phosphoinositide 3-kinase; mTOR: mammalian target of rapamycin; PTEN: phosphatase and tensin homolog.

3.3. PARP Inhibitors

The prevalence of BRCA (Breast Cancer genes) mutations in TNBC patients is approximately 20% [193]^[34]. BRCA1 and BRCA2 are proteins involved in the DNA damage response to repair DNA lesions [194]^[35]. Mutations in BRCA 1/2 genes are associated with an increased risk of breast and ovarian cancers [195]^[36]. PARP (poly-(ADP-ribose) polymerase protein) proteins are also involved in the DNA damage response as they recruit DNA repair proteins, such as BRCA1 and BRCA2, to the damage site [196]^[37]. PARP inhibitors (PARPi) were developed to inhibit DNA repair in BRCA-mutated BC since cells defective in BRCA functions cannot repair DNA damage when PARP is inhibited [197]^[38]. The principal PARPis currently in clinical development are olaparib, talazoparib, veliparib, and rucaparib [198]^[39]. PARP inhibitors mechanisms of action and resistance are described in Figure 5.

Figure 5. PARP inhibitors mechanisms of action and resistance. The left part of the figure describes the mechanism of PARP inhibitors in the context of BRCA mutated breast cancer. The right part of the figure describes the mechanism of resistance to PARP inhibitors through secondary intragenic mutations restoring BRCA proteins functions and the decrease of the recruitment of nucleases (MUS81 or MRE11) to protect the replication fork. PARP: poly-(ADP-ribose) polymerase protein; PARPi: PARP inhibitors; BRCA: breast cancer protein; MUS81: methyl methanesulfonate ultraviolet sensitive gene clone 81; MRE11: meiotic recombination 11.

4. New Strategies and Challenges for Breast Cancer Treatment

4.1. Emerging Therapies for HR-Positive Breast Cancer

The major mechanisms of action of current endocrine therapy resistance occur via (1) the mTOR/PI3K/Akt signaling pathway and (2) the actors of the cell cycle progression CDK4/6. Therefore, emerging therapies for HR+ BC mainly target the actors of these pathways to bypass estrogen-independent cell survival [229]^[40]. The most recent completed clinical trials on emerging therapies for HR+ BC are presented in Table 1.

Table 1. Most recent completed clinical trial on emerging therapies for HR-positive breast cancer.

	Targeted Therapy			Drug Name

Most recent completed clinical trials on emerging therapies for HER2+ breast cancer.

	Targeted Therapy			Drug Name		Trial Number			Trial Number		Patient Population			Trial Arms			Outcomes
		Drug Name		Patient Population			Trial Number			Patient Population		Trial Arms			Outcomes
	Trial Arms			Outcomes
	Pan-PI3K inhibitors
					Antibodies drug conjugate (ADC)		Buparlisib			Trastuzumab-deruxtcan
					Antibodies drug conjugate (ADC)					Antibodies Drug Conjugate		(DS-8201a)			Sacituzumab govitecan		BELLE-2		Phase III		NCT01610284 [ 230]		DESTINY-Breast01	^[	Phase II		NCT03248492 [ 264]	^[ ⁶⁴ ^]		ASCENT		Phase III	⁴¹ ^]		NCT02574455 [ 309]	^[ ⁸¹ ^]	HR+/HER2-		Postmenopausal		Locally advanced or MBC		HER2+ Prior AI treatment			MBC		Buparlisib + fulvestrant vs. placebo + fulvestrant		Prior trastuzumab-emtansine treatment		PFS 6.9 months vs. 5.0 months (HR 0.78; p			TNBC		MBC		Prior standard treatmentTrastuzumab-deruxtcan monotherapy		= 0.00021)		Sacituzumab govitecan vs. single-agent chemotherapy	PFS 6.8 months vs. 4.0 months in PI3K mutated (HR 0.76; p = 0.014)
				PFS 16.4 months					BELLE-3		Phase III		NCT01633060 [ 231]
				PFS 5.6 months vs. 1.7 months (HR 0.41;	p	< 0.001)		PFS 12.1 months vs. 6.7 months (HR 0.48; p < 0.001)			^[ ⁴² ^]			Trastuzumab-duocarmycin (SYD985)		HR+/HER2-		Postmenopausal		Locally advanced or MBC
	VEGF inhibitors			Phase I dose-escalation and dose-expansion		NCT02277717 Prior endocrine therapy or mTOR inhibitors		[ 265]	^[ ^65]	Buparlisib + fulvestrant vs. placebo + fulvestrant		Bevacizumab				PFS 3.9 months vs. 1.8 months (HR 0.67; p = 0.0003)
	VEGF inhibitors		HER2+		Locally advanced or metastatic solid tumors			BEATRICE		Phase III		Bevacizumab			NCT00528567 [ 310]	^[ ⁸² ^]	Trastuzumab-duocarmycin monotherapy			Early TNBC		Surgery		ORR 33%			BELLE-4		Phase II/III		NCT01572727 [ 232]	^[
	Bevacizumab + chemotherapy vs. chemotherapy alone			IDFS 80% vs. 77%		OS 88% vs. 88%		⁴³ ^]		Modified antibodies
	CALGB 40603		Phase II		NCT00861705 [ 311		HER2-		Locally advanced or MBC		No prior chemotherapy		]	^[ ⁸³ ^]	Margetuxumab (MGAH22)				TNBC		Stage II to IIIBuparlisib + pacliatxel vs. placebo + paclitaxel			SOPHIA		Phase III		NCT02492711 [ 266]	^[ ⁶⁶ ^]	PFS 8.0 months vs. 9.2 months (HR 1.18, 95% CI 0.82–1.68)		PFS 9.1 months vs. 9.2 months in PI3K mutated (HR 1.17, 95% 0.63–2.17)
	HER2+			Bevacizumab + chemotherapy vs. chemotherapy alone or Carboplatin + chemotherapy vs. chemotherapy alone Advanced or MBC		Prior anti-HER2 therapies				pCR 59% vs. 48% (p = 0.0089) (Bevacizumab)		pCR 60% vs. 44% ( p = 0.0018) (Carboplatin)		Margetuximab + chemotherapy vs. trastuzumab + chemotherapy			PFS 5.8 months vs. 4.9 months (HR 0.76; p = 0.03)		OS 21.6 months vs. 19.8 months (HR 0.89; p = 0.33)		ORR 25% vs. 14% ( p < 0.001)			Pictilisib			FERGI		Phase II		NCT01437566 [ 233]	^[ ⁴⁴ ^]		HR+/HER2-		Postmenopausal		Prior AI treatment			Pictilisib + fulvestrant vs. placebo + fulvestrant			PFS 6.6 months vs. 5.1 months (HR 0.74; p = 0.096)		PFS 6.5 months vs. 5.1 months in PI3K mutated (HR 0.74; p = 0.268)		PFS 5.8 months vs. 3.6 months in non-PI3K mutated (HR 0.72; p = 0.23)
	PEGGY		Phase II		NCT01740336 [ 234]	^[ ⁴⁵ ^]		HR+/HER2-		Locally recurrent		or MBC			Pictilisib + paclitaxel vs. placebo + paclitaxel			PFS 8.2 months vs. 7.8 months (HR 0.95; p = 0.83)		PFS 7.3 months vs. 5.8 months in PI3K mutated (HR 1.06; p = 0.88)				Pictilisib
	Isoform-specific inhibitors			Alpelisib			Phase Ib		NCT01791478 [235]	^[ ^46]		HR+/HER2-		Postmenopausal		MBC		Prior endocrine therapy			Alpelisib + letrozole			CBR 35% (44% in patients with PIK3CA mutated and 20% in PIK3CA wild-type tumors; 95% CI [17%; 56%])
							SOLAR-1		Phase III		NCT02437318 [ 236]	^[ ⁴⁷ ^]		HR+/HER2-		Advanced BC		Prior endocrine therapy			Alpelisib + fulvestrant vs. placebo + fulvestrant			PFS 7.4 months vs. 5.6 months in non-PI3K mutated (HR 0.85, 95% CI 0.58–1.25)		PFS 11.0 months vs. 5.7 months in PI3K mutated (HR 0.65; p = 0.00065)
							NEO-ORB		Phase II		NCT01923168 [ 237]	^[ ⁴⁸ ^]		HR+/HER2-		Postmenopausal		Early-stage BC		Neoadjuvant setting			Alpelisib + letrozole vs. placebo + letrozole			ORR 43% vs. 45% (PIK3CA mutant), 63% vs. 61% (PIK3CA wildtype)		pCR rates low in all groups
				Taselisib			SANDPIPER		Phase III		NCT02340221 [ 238]	^[ ⁴⁹ ^]		HR+/HER2-		Postmenopausal		Locally advanced or MBC		PIK3CA-mutant		Prior AI treatment			Taselisib + fulvestrant vs. placebo + fulvestrant			PFS 7.4 months vs. 5.4 months (HR 0.70; p = 0.0037)
				Taselisib			LORELEI		Phase II		NCT02273973 [ 239]	^[ ⁵⁰ ^]		HR+/HER2-		Postmenopausal		Early-stage BC		Neoadjuvant setting			Taselisib + letrozole vs. placebo + letrozole			ORR 50% vs. 39.3% (OR 1.55; p = 0.049)		ORR 56.2% vs. 38% in PI3K mutated (OR 2.03; p = 0.033)		No significant difference in pCR
	mTOR inhibitors			Everolimus			BOLERO-2		Phase III		NCT00863655 [ 240]	^[ ⁵¹ ^]		HR+/HER2-		Advanced BC		Prior AI treatment			Everolimus + exemestane		vs. placebo + exemestane			PFS 6.9 months vs. 2.8 months (HR 0.43; p < 0.001)
							TAMRAD		Phase II		NCT01298713 [ 241]	^[ ⁵² ^]		HR+/HER2-		Postmenopausal		MBC		Prior AI treatment			Everolimus + tamoxifen vs. tamoxifen alone			CBR 61% vs. 42%		TTP 8.6 months vs. 4.5 months (HR 0.54)
							Tyrosine kinase inhibitors			Tucatinib			HER2CLIMB		Phase II		NCT02614794 [ 267]
	EGFR inhibitors			Cetuximab			Tyrosine kinase inhibitors			^[ ⁶⁷ ^]		TBCRC 001		Phase II		NCT00232505 [ 312]	^[ ⁸⁴ ^]	HER2+		Locally advanced or MBC		Prior anti-HER2 therapies				TNBC		MBC		Tucatinib + trastuzumab and capecitabine vs. placebo + trastuzumab and capecitabine				Cetuximab + carboplatin		PFS 33.1% (7.8 months) vs. 12.3% (5.6 months) (HR 0.54; p < 0.001)		PFS 24.9% vs. 0% (HR 0.48; p < 0.001) in brain metastases patients		OS 44.9% vs. 26.6% (HR 0.66; p = 0.005)
	EGFR inhibitors			Cetuximab			Response < 20%		TTP 2.1 months			Poziotinib
	Phase II		NCT00463788 [313]	^[ ^85]	NOV120101-203		Phase II		NCT02418689 [ 268		TNBC ]	^[ ⁶⁸ ^]		MBC		Prior chemotherapy treatment		HER2+		MBC		Prior chemotherapy and trastuzumab				Cetuximab + cisplatin vs. cisplatin alone		Poziotinib monotherapy			PFS 4.04 months
	ORR 20% vs. 10% (	p	= 0.11)		PFS 3.7 months vs. 1.7 months (HR 0.67; p = 0.032)		OS 12.9 months vs. 9.4 months (HR 0.82; p = 0.31)			HER2-derived peptide vaccine
	mTORC1 inhibitors		E75 (NeuVax)			Everolimus		Phase I/II					NCT00841399		NCT00854789 [ 269]	^[ ⁶⁹ ^]		Phase II		NCT00930930 [314]	^[ ^86]	HER2+		Node-positive or high-risk node-negative BC		HLA2/3+			E75 vaccination vs. non-vaccination				TNBC		Stage II or III		Neoadjuvant treatment			Everolimus + cisplatin and paclitaxel vs. placebo + cisplatin and paclitaxel		DFS 89.7% vs. 80.2% (p = 0.008)		DFS 94.6% in optimal dosed patients ( p = 0.005 vs. non-vaccination)
	pCR 36% vs. 49%			GP2
	Akt inhibitors		Phase II		NCT00524277 [270]	^[ ^70]		HER2 (IHC 1-3+)		Disease free		Node-positive or high-risk node-negative BC		HLA2+			GP2 + GM-CSF vs. GM-CSF alone			DFS 94% vs. 85% (p = 0.17)		DFS 100% vs. 89% in HER2-IHC3+ ( p = 0.08)
				Ipatasertib			LOTUS		Phase II		NCT02162719 [ 315]	^[ ⁸⁷ ^]		TNBC		Locally advanced or MBC		No prior sytemic therapy			Ipatasertib + paclitaxel vs. placebo + paclitaxel			PFS 6.2 months vs. 4.9 months (HR 0.60;		AE37			Phase II		NCT00524277 [271]	^[ ^71]		HER2 (IHC 1-3+)		Node-positive or high-risk node-negative BC			AE37 + GM-CSF vs. GM-CSF alone			DFS 80.8% vs. 79.5% (p = 0.70)		DFS 77.2% vs. 65.7% ( p = 0.21) HER2-low		DFS 77.7% vs. 49.0% ( p = 0.12) TNBC
				Ipatasertib		p	= 0.037)		PFS 6.2 months vs. 3.7 moths (HR 0.58;	p	= 0.18) in PTEN-low patients
	FAIRLANE		Phase II		NCT02301988 [ 316]	^[ ⁸⁸ ^]		Early TNBC		Neoadjuvant treatment			Ipatasertib + paclitaxel vs. placebo + paclitaxel			pCR 17% vs. 13%		pCR 16% vs. 13% PTEN-low patients		pCR 18% vs. 12% PIK3CA/AKT1/PTEN-altered patients			PI3K inhibitors
	Capivasertib			Alpelisib				PAKT		Phase II		NCT02423603 [ 317]	^[ ⁸⁹ ^]	Phase I		NCT02167854 [272]	^[ ^72]		TNBC		MBC					No prior chemotherapy treatment		HER2+		Capivasertib + paclitaxel vs. placebo + paclitaxel MBC with a PIK3CA mutation Prior ado-trastuzumab emtansine and pertuzumab			Alpelisib + Trastuzumab + LJM716				PFS 5.9 months vs. 12.6 months (HR 0.61; Toxicities limited drug delivery 72% for alpelisib 83% for LJM716
p	= 0.04)			Alpelisib			Phase I		NCT02038010 [273]	^[ ^73]
	Androgen receptor inhibitors		HER2+		MBC		Prior trastuzumab-based therapy			Bicalutamide		Alpelisib + T-DM1			Phase II		NCT00468715 [318]	^[ ⁹⁰	PFS 8.1 months		ORR 43%		CBR 71% and 60% in prior T-DM1 patients
	Androgen receptor inhibitors		^]			HR-		AR+ or AR-		MBC			Bicalutamide monotherapy			CBR 19%		PFS 12 weeks			Copanlisib
	Enzalutamide		PantHER		Phase Ib		NCT02705859 [ 274]			Phase II		NCT01889238 [319]	^[ ⁷⁴ ^]		^[ ^91]	HER2+		Advanced BC		Prior anti-HER2 therapies			TNBC		AR+		Locally advanced or MBC		Copanlisib + trastuzumab			Stable disease 50%
	Enzalutamide monotherapy			CBR 25%		OS 12.7 months			mTOR inhibitors			Everolimus			BOLERO-1		Phase III		NCT00876395 [ 275]	^[ ⁷⁵ ^]		HER2+		Locally advanced BC		No prior treatment			Everolimus + trastuzumab vs. placebo + trastuzumab
	CYP17 inhibitors			PFS 14.95 months vs. 14.49 months (HR 0.89;	p = 0.1166)		PFS 20.27 months vs. 13.03 months (HR 0.66; p = 0.0049)		mTOR inhibitors			Everolimus				PrE0102		Phase II		NCT01797120 [ 242]
	Abiraterone acetate			UCBG 12-1		Phase II		NCT01842321 [ 320]	^[ ⁹² ^]		TNBC		AR+		Locally advanced or MBC		Centrally reviewed		Prior chemotherapy			Abiraterone acetate + prednisone			CBR 20%		ORR 6.7%		PFS 2.8 months			BOLERO-3		Phase III	^[ ⁵³ ^]		NCT01007942 [ 276]	^[ ⁷⁶ ^]	HR+/HER2-		Postmenopausal		MBC		Prior AI treatment			HER2+		Advanced BC		Trastuzumab-resistant		Everolimus + fulvestrant		vs. placebo + fulvestrant			Prior taxane therapy		PFS 10.3 months vs. 5.1 months (HR 0.61;
	Anti-PDL1 antibodies			Atezolizumab			Everolimus + trastuzumab and vinorelbine vs. placebo + trastuzumab and vinorelbine			Impassion 130		Phase III		NCT02425891 [ 321]	^[ ⁹³ ^]	p = 0.02)		CBR 63.6% vs. 41.5% ( p = 0.01)
				Atezolizumab			PFS 7.00 months vs. 5.78 months (HR 0.78;	p	= 0.0067)			TNBC		Locally advanced or MBC		No prior treatment			Atezolizumab + nab-paclitaxel vs. placebo + nab-paclitaxel			OS 21.0 months vs. 18.7 months (HR 0.86; p = 0.078)		OS 25.0 months vs. 18.0 months (HR 0.71, 95% CI 0.54–0.94)) in PDL-1+ patients			Akt inhibitors			Capivasertib
						CDK4/6 inhibitors																					Akt inhibitors			Capivasertib
								Impassion 031		Phase III		NCT03197935 [ 322]	^[ ⁹⁴ ^]	FAKTION		Phase II		NCT01992952		TNBC		Stage II to III		No prior treatment		[ 243 ]	^[ ⁵⁴ ^]		Palbociclib			SOLTI-1303 PATRICIA		Phase II		NCT02448420 [ 277]	^[ ⁷⁷ ^]		Atezolizumab + chemotherapy vs. placebo + chemotherapy		HR+/HER2-			pCR 95% vs. 69% Postmenopausal		Locally advanced or MBC		Prior AI treatment				HER2+		ER+ or ER-		p MBC		= 0.0044 Prior standard therapy including trastuzumab		Capivasertib + fulvestrant vs. placebo + fulvestrant		PFS 10.3 months vs. 4.8 months (HR 0.57; p = 0.0035)
				Palbociclib + trastuzumab						PFS 10.6 months (luminal) vs. 4.2 months (non-luminal) (HR 0.40;	p = 0.003)			Phase I		NCT01226316 [244]	^[ ^55]
				Ribociclib
	Durvalumab			ER+		AKT1 ^E17K-mutant		MBC		Prior endocrine treatment			Phase Ib/II		NCT02657343 [278]	^[ ^78]	Capivasertib + fulvestrant vs. Capivasertib alone				GeparNuevo		Phase II		NCT02685059HER2+		Advanced BC		Prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine		CBR 50% vs. 47%		ORR 6% (fulvestrant-pretreated) and 20% (fulvestrant-naïve) vs. 20%
				Ribociclib + trastuzumab		[ 323 ]	^[ ⁹⁵ ^]	PFS 1.33 months			TNBC		MBC		Stromal tumor-infiltrating lymphocyte (sTILs)			Durvalumab vs. placebo		No dose-limiting toxicities			pCR 53.4% vs. 44.2%		pCR 61.0% vs. 41.4% in window cohort			CDK4/6 inhibitors
				SAFIRO BREAST-IMMUNO		Phase II		NCT02299999 [ 324
	Abemaciclib		Palcociclib		]	^[ ⁹⁶	MonarcHER			Phase II		NCT02675231 [ 279]	^[ ⁷⁹ ^]	PALOMA-1		Phase II		NCT00721409 [ 126]	^[ ⁵⁶ ^]		HR+/HER2-		Postmenopausal		Advanced BC					No prior systemic treatment			Palbocilib + letrozole vs. letrozole alone				HER2+		Locally advanced or MBC		Prior anti-HER2 therapies			Abemaciclib + trastuzumab and fulvestrant (A) vs. abemaciclib + trastuzumab (B) vs. standard-of-care chemotherapy + trastuzumab (C)			PFS 8.3 months (A) vs. 5.7 months (C) (HR 0.67; p = 0.051)		PFS 5.7 months (B) vs. 5.7 months (C) (HR 0.97; p = 0.77)		PFS 20.2 months vs. 10.2 months (HR 0.488; p = 0.0004)		PFS 26.1 months vs. 5.7 months (HR 0.299; p < 0.0001) in non-Cyclin D1 amplified		PFS 18.1 months vs. 11.1 months (HR 0.508; p = 0.0046) in Cyclin D1 amplified
	PALOMA-2				Phase III		NCT01740427 [ 245]	^[ ⁵⁷ ^]			HR+/HER2-		Postmenopausal		Advanced BC		No prior systemic treatment			Palbocilib + letrozole vs. placebo + letrozole			PFS 24.8 months vs. 14.5 months (HR 0.58; p < 0.001)
	PALOMA-3				Phase III		NCT01942135 [ 246]	^[ ⁵⁸ ^]		HR+/HER2-		MBC		Prior endocrine therapy			Palbociclib + fulvestrant		vs. placebo + fulvestrant			PFS 9.5 months vs. 4.6 months (HR 0.46; p < 0.0001)
	Ribociclib			MONALEESA-2		Phase III		NCT01958021 [ 247]	^[ ⁵⁹ ^]		HR+/HER2-		Postmenopausal		Advanced or MBC			Ribociclib + letrozole vs. placebo + letrozole			PFS 25.3 months vs. 16.0 months (HR 0.568; p < 0.0001)
	Ribociclib			MONALEESA-3		Phase III		NCT02422615 [ 248]	^[ ⁶⁰ ^]		HR+/HER2-		Advanced BC		No prior treatment or prior endocrine therapy			Ribociclib + fulvestrant vs. placebo + fulvestrant			PFS 20.5 months vs. 12.8 months (HR 0.593; p < 0.001)
	Abemaciclib			MONARCH-2		Phase III		NCT02107703 [ 249]	^[ ⁶¹ ^]		HR+/HER2-		Advanced or MBC		Prior endocrine treatment			Abemaciclib + fulvestrant vs. fulvestrant alone			PFS 16.4 months vs. 9.3 months (HR 0.553; p < 0.001)
	Abemaciclib			MONARCH-3		Phase III		NCT02246621 [ 250]	^[ ⁶² ^]		HR+/HER2-		Advanced or MBC		Prior endocrine treatment			Abemaciclib + anastrozole or letrozole vs. placebo + anastrozole or letrozole			PFS 28.18 months vs. 14.76 months (HR 0.546; p < 0.0001)

HR+: hormone receptors positive; HER2-: human epidermal growth factor receptor 2 negative; MBC: metastatic breast cancer; BC: breast cancer; PFS: progression free survival; CBR: clinical benefit rate; ORR: objective response rate; pCR: pathologic complete response; HR: hazard ratio.

4.2. New Strategic Therapies for HER2-Positive Breast Cancer

HER2+ BC is currently treated with specific HER2 targeting antibodies or tyrosine kinase inhibitors (TKIs), and more recently, with TDM-1, an antibody-drug conjugate. These treatments have greatly improved HER2+ BC survival. However, 25% of HER2+ BC patients will still develop resistance to anti-HER2 treatment. Hence, new therapeutic strategies are emerging, such as new antibodies targeting HER2, new TKIs, vaccines, and PI3K/mTOR and CDK4/6 inhibitors [263]^[63]. The most recent completed clinical trials on new strategies for HER2+ BC treatment are gathered in Table 2.

Table 2.

HER2+: human epidermal growth factor receptor 2 positive; ER+: estrogen receptor positive; HLA2/3: human leucocyte antigen 2/3; MBC: metastatic breast cancer; BC: breast cancer; PFS: progression free survival; CBR: clinical benefit rate; ORR: objective response rate; DFS: disease-free survival OS: overall survival GM-CSF: granulocyte macrophage colony-stimulated factor; HR: hazard ratio.

4.3. Emerging Therapies for Triple Negative Breast Cancer (TNBC)

TNBC is the most aggressive BC subtype. The fact that TNBC lacks ER and PR expression and does not overexpress HER2, combined with its high heterogeneity, has contributed to the difficulties in developing efficient therapies [308]^[80]. Thus, multiple strategic therapies have been developed to treat all TNBC subtypes. These include conjugated antibodies, targeted therapy, and immunotherapy. An overview of the most recent and completed clinical trials on emerging therapies for TNBC is presented in Table 3.

Table 3. Most recent completed clinical trials on emerging therapies for TNBC.

	Targeted Therapy
^]


HER2-

MBC

Prior chemotherapy


Durvalumab vs. maintenance chemotherapy

	HR of death 0.37 for PDL-1+ patients	HR of death 0.49 for PDL-1- patients
	Phase I	NCT02484404 [325]	^[ ^97]	Recurrent women’s cancers including TNBC			Durvalumab + cediranib + olaparib			Partial response 44%		CBR 67%
	Avelumab		JAVELIN	Phase Ib		NCT01772004 [ 326]	^[ ⁹⁸ ^]		MBC		Prior standard-of-care therapy		Avelumab monotherapy		ORR 3.0% overall	ORR 5.2% in TNBC		ORR 16.7% in PDL-1+ vs. 1.6% in PDL-1- overall		ORR 22.2.% in PDL-1+ vs. 2.6% in PDL-1- in TNBC
	Anti-PD1 antibodies		Pembrolizumab		KEYNOTE-086		Phase II		NCT02447003 [ 327]	^[ ⁹⁹ ^]		TNBC	MBC	Prior or no prior systemic therapy		Pembrolizumab monotherapy			Previously treated patients:		ORR 5.3% overall	ORR 5.7% PDL-1+ patients	PFS 2.0 months	OS 9.0 months	Non-previously pretreated:	ORR 21.4%	PFS 2.1 months	OS 18.0 months
					KEYNOTE-119		Phase III		NCT02555657 [ 328]	^[ ¹⁰⁰ ^]		TNBC	MBC	Prior systemic therapy		Pembrolizumab vs. chemotherapy			OS 12.7 months vs. 11.6 months (HR 0.78; p = 0.057) in PDL1+ patients		OS 9.9 months vs. 10.8 months (HR 0.97, 95% CI 0.81–1.15)
					KEYNOTE-355		Phase III		NCT02819518 [ 329]	^[ ¹⁰¹ ^]		TNBC	MBC	No prior systemic therapy		Pembrolizumab + chemotherapy vs. placebo + chemotherapy			PFS 9.7 months vs. 5.6 months (HR 0.65; p = 0.0012) in PDL-1+ patients		PFS 7.6 months vs. 5.6 months (HR 0.74; p = 0.0014)
					KEYNOTE-522		Phase III		NCT03036488 [ 330]	^[ ¹⁰² ^]		Early TNBC	Stage II to III	No prior treatment		Pembrolizumab + paclitaxel and carboplatin vs. placebo + paclitaxel and carboplatin			pCR 64.8% vs. 51.2 % (p < 0.001)
	Anti-CDL4 antibodies		Tremelimumab		Phase I [331]	^[103]		Incurable MBC			Tremelimumab + radiotherapy		OS 50.8 months
	Vaccines		PPV		Phase II		UMIN000001844 [332]	^[ ^104]		TNBC		MBC	Prior systemic therapy		PPV vaccine		PFS 7.5 months		OS 11.1 months
	Vaccines		STn-KLH		Phase III		NCT00003638 [333]	^[ ^105]		MBC		Prior chemotherapy	Partial or complete response		STn-KLH vaccine vs. non-vaccine		TTP 3.4 months vs. 3.0 months

TNBC: triple negative breast cancer; HER2: human epidermal growth factor receptor; HR: hormonal receptor; MBC: metastatic breast cancer; BC: breast cancer; AR: androgen receptor; PPV: personalized peptide vaccine; PFS: progression free survival; CBR: clinical benefit rate; ORR: objective response rate; IDFS: invasive disease-free survival; OS: overall survival; TTP: time to progression; pCR: pathologic complete response; HR: hazard ratio.

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